Omeprazole Mups®: an Advanced Formulation Offering Flexibility and Predictability for Self Medication

SUPPLEMENT SelfCare 2011;2(S1):1-14

The journal ofconsumer-led health

OMEPRAZOLE MUPS®: AN ADVANCED FORMULATION OFFERING FLEXIBILITY AND PREDICTABILITY FOR SELF MEDICATION

JÉRÔME AUBERT*, CHRIS J. J. MULDER†, KARSTEN SCHRÖR**, STEPHAN R. VAVRICKA†† *Head, Formulation Development, Bayer Santé Familiale S.A.S., France †VU University Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, Netherlands **Direktor em., Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine Universität, Düsseldorf, Germany ††Head, Division of Gastroenterology and Hepatology, Stadtspital Triemli, Zurich, Switzerland

ABSTRACT INTRODUCTION: The MUPS®* tablet formulation of omeprazole magnesium is now in widespread use as a consumer medicine in Europe and the United States (US). On December 8th 2010 a panel of experts was assembled in Zurich to review the accumulated evidence on omeprazole MUPS® and the contribution of the pharmaceutical, pharmacokinetic and pharmacodynamic features of this formulation to clinical efficacy in the treatment of symptomatic reflux disease.

FORMULATION: The MUPS® tablet is a patented formulation of omeprazole designed to optimise delivery of omeprazole to the site of its absorption in the small intestine. In particular the gastro-resistant properties of the multiple layered micropellets are important to protect the acid-labile omeprazole from gastric juice. Many generic omeprazole formulations are now available for consumer purchase in some European markets. Dissolution studies with a variety of omeprazole formulations confirm substantial differences in speed and degree of omeprazole release under differing pH conditions designed to mimic gastric passage and duodenal delivery. Omeprazole formulations available for consumers to purchase cannot be considered interchangeable with regard to pharmaceutical properties.

PHARMACOKINETICS AND PHARMACODYNAMICS: Omeprazole is an inactive prodrug which requires nonenzymatic, proton-catalyzed conversion to an active sulphenamide intermediate in the secretory cannaliculi of the parietal cell, this then binds to and inactivates the H+K+-ATPase ‘proton pump’. Omeprazole MUPS® tablets are bioequivalent to the originally marketed omeprazole capsules and produce similar pharmacodynamic effects on gastric secretion in direct comparison studies. In comparison to capsules, however, bioavailability from the MUPS® tablet is somewhat faster in the fed state. Bioavailability of omeprazole increases between day 1 and day 6 of dosing and this is reflected in an increased pharmacodynamic effect (median gastric pH) compared to pantoprazole 40mg at day 6 but an equivalent effect on day 1.

HEARTBURN STUDIES IN CONSUMERS: Heartburn is very common in the general population and 20% of sufferers have symptoms more often than weekly. Endoscopy is not warranted in these individuals unless ‘alarm’ symptoms (e.g. anaemia, dysphagia, weight loss) are present. In surveys, frequent sufferers want complete and long lasting relief from heartburn. Large clinical studies with the MUPS® formulation in the US confirm that high proportions of both day and night time periods are reported as free of heartburn on regular dosing for 14 days with omeprazole MUPS® 20mg and 10mg. A naturalistic study of consumer compliance with US label instructions for omeprazole MUPS® showed that self-selection for treatment

*MUPS® is a registered trademark of the AstraZeneca group of companies. The MUPS® tablet is protected by patent property owned by the AstraZeneca group of companies and distributed under licence by Bayer Consumer Care.

©SELFCARE MAY 2011 Accepted for publication March 2011 S1 OMEPRAZOLE MUPS®: AN ADVANCED FORMULATION FOR SELF MEDICATION

was appropriate in the great majority of participants and very few exceeded the mandated 14 days of treatment without medical advice.

PRESCRIPTION EXPERIENCE WITH MUPS® AND GENERIC OMEPRAZOLE: In the Netherlands, a large study comparing omeprazole MUPS® 20mg, lansoprazole 30mg and pantoprazole 40mg in patients with symptomatic grade I-IV reflux oesophagitis confirmed similar high levels of patient satisfaction with all drugs after 4 and 8 weeks. The popularity of PPIs for acid related conditions in the Netherlands, as elsewhere, has led to increasing levels of usage and an associated rise in costs. Since the loss of patent protection in 2004, more than 50 generic versions of omeprazole have been launched in the Netherlands. Studies of omeprazole release characteristics from examples of these preparations show variable rates of drug delivery and some evidence that ‘dose dumping’ may occur and potentially affect efficacy. The absorption, distribution and activation of omeprazole in functioning proton pumps is a complex series of processes that may not be adequately represented by narrowly defined bioequivalence determined on pharmacokinetic grounds. The suggestion that generic formulations may exhibit pharmacodynamic and clinical differences compared to the originator drug, is lent some indirect support by the results of a survey of 5,254 users of generic omeprazole in the Netherlands. This found that around 20% of users required substitution of originator omeprazole or another PPI on grounds of unsatisfactory response to generic omeprazole treatment.

SUMMARY: The omeprazole MUPS® formulation is a carefully designed galenic form which optimises delivery of the drug to the site of activation and pharmacodynamic action, particularly in the fed state. The small easily swallowed tablet can also be dispersed in water. This formulation has been well characterised in pharmacokinetic, pharmacodynamic and clinical studies. In particular omeprazole MUPS® has been shown to produce substantial freedom from heartburn in a frequently suffering population during 14 days of use. When recommending a PPI for appropriate consumers, health care professionals should consider this level of evidence and be aware that not all omeprazole formulations can be considered as interchangeable in clinical use.

Key words: Omeprazole, MUPS®, Gastro-resistant formulation, Bioequivalence.

FEATURES OF THE MUPS® FORMULATION - Jérôme Aubert, Pharm D Head, Formulation Development, Bayer Santé Familiale S.A.S., France

Omeprazole is a pro-drug that accumulates in the acid space of the parietal cell where it is transformed to the active state. However the drug has several characteristics which determine its access to this site of action. Omeprazole is a weak base which is stable at neutral pH but decomposes rapidly in an acidic environment. Therefore, in order for it to reach the small intestine where it is absorbed, it must be protected from gastric fluid when administered orally. These properties pose challenges for drug formulators seeking to provide optimal delivery of the drug.

The MUPS® tablet formulation of omeprazole employs patented technology in a delivery system which disperses rapidly in the stomach to release about 1,000 small (0.5mm) individually enteric coated units or ‘micropellets’ of omeprazole as the magnesium salt. These pellets are designed to dissolve in the high pH of the small intestine to release omeprazole for absorption.

©SELFCARE MAY 2011 Accepted for publication March 2011 S2 OMEPRAZOLE MUPS®: AN ADVANCED FORMULATION FOR SELF MEDICATION

The manufacture of MUPS® tablets has multiple steps. First omeprazole magnesium is micronized before suspension and layering onto sugar microspheres (0.250-0.355mm). These pellets are then sub-coated to separate the omeprazole from the enteric coating which is applied next. The pellets are then given a final protective over-coating before being mixed with tabletting excipients and compressed into tablets which themselves are film-coated.

Thus each MUPS® pellet has a 4 layer ‘onion’ structure and each tablet is comprised of multiple pellets which are apparent if the tablet is broken (figure 1).

FIGURE 1: PELLET STRUCTURE APPARENT IN BROKEN MUPS® TABLETS.

In vitro dissolution testing of the tablets confirms the USP specifications required to meet the key formulation characteristic of gastro-resistance. In the first or ‘gastric phase’, dissolution of the tablets in acid pH 1 (HCl 0.1 M) stirred for 2 hours (100 rpm paddle speed) is measured, and not less than 90% of the omeprazole content should remain intact in the pellets. Subsequently in the ‘small intestine’ or drug release phase, dissolution at pH 6.8 is measured and after 45 minutes not less than 75% of the stated omeprazole content should be released. Changes in the quantity of enteric coating and protective overcoating can be shown to have an effect on gastric resistance as can tablet hardness which varies with the punch force used to produce the tablets.

Since the expiry of the patent on omeprazole, numerous generic copies have been marketed. The introduction of omeprazole as a non-prescription or ‘over the counter’ (OTC) medicine in some countries has also led to an explosion in the availability of alternative generic versions. For example in Germany there are more than 20 ‘OTC’ formulations of omeprazole although only a few of these are tablets (one of which is the Bayer MUPS® product) with the majority being capsule formulations.

The pharmaceutical quality and properties of these generic products may vary and analytical techniques to examine them (e.g. the dissolution testing described above) may not be very discriminative. A study of the pharmaceutical quality of 7 local omeprazole capsule brands in Egypt was assessed relative to the proprietary product (Losec®)1. All brands passed the USP drug release test (omeprazole release from capsules at pH 6.8 after pre-exposure to pH 1 for 2 hours) as shown in Figure 2. However a modified release test (omeprazole release profile at pH 6.8 after pre-exposure to pH 4 for 2 hours) proved to be more discriminative between formulations (see Figure 3). Pre-exposure to this latter pH may reflect more closely both the gastric pH after food and during ongoing acid suppression with omeprazole.

©SELFCARE MAY 2011 Accepted for publication March 2011 S3  

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OMEPRAZOLE MUPS®: AN ADVANCED FORMULATION FOR SELF MEDICATION

FIGURE 2: RELEASE PROFILE OF DIFFERENT BRANDS OF OMEPRAZOLE CAPSULES AT PH 6.8 AFTER PRE-EXPOSURE TO PH 1 FOR 2 HOURS (Adapted from Reference 1). 

 

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  FIGURE 3: RELEASE PROFILE OF DIFFERENT BRANDS OF OMEPRAZOLE CAPSULES AT PH 6.8 AFTER PRE-EXPOSURE TO PH 4 FOR 2 HOURS (Adapted from Reference 1). ﺍﳌﺠﻠﺔ ﺍﻟﺼﺤﻴﺔ ﻟﺸﺮﻕ ﺍﳌﺘﻮﺳﻂ، ﻣﻨﻈﻤﺔ ﺍﻟﺼﺤﺔ ﺍﻟﻌﺎﳌﻴﺔ، ﺍﳌﺠﻠﺪ ﺍﻟﺜﺎﻟﺚ ﻋﺸﺮ، ﺍﻟﻌﺪﺩ ٦، ٢٠٠٧

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 



ﺍﳌﺠﻠﺔ ﺍﻟﺼﺤﻴﺔ ﻟﺸﺮﻕ ﺍﳌﺘﻮﺳﻂ، ﻣﻨﻈﻤﺔ ﺍﻟﺼﺤﺔ ﺍﻟﻌﺎﳌﻴﺔ، ﺍﳌﺠﻠﺪ ﺍﻟﺜﺎﻟﺚ ﻋﺸﺮ، ﺍﻟﻌﺪﺩ ٦، ٢٠٠٧

  In this study and others2,3 using a stability test performed under accelerated conditions (40 degrees Centigrade, 75% relative humidity, during a four month period) the investigators capsule formulations was ﺍﳌﺠﻠﺔsome ﺍﻟﺼﺤﻴﺔfrom ﻟﺸﺮﻕ ﺍﳌﺘﻮﺳﻂ،pellets ﻣﻨﻈﻤﺔthe ﺍﻟﺼﺤﺔof ﺍﻟﻌﺎﳌﻴﺔ، ﺍﳌﺠﻠﺪ ﺍﻟﺜﺎﻟﺚdarkening ﻋﺸﺮ، ﺍﻟﻌﺪﺩ ٦، concluded that progressive٢٠٠٧ associated with very low dissolution performance.

SUMMARY

The omeprazole MUPS® tablet formulation (protected by a patent valid until 2014) is an innovative product designed to deliver the maximal amount of omeprazole to the site of absorption in the small intestine by protecting it in micropellets during passage through the stomach. Although

©SELFCARE MAY 2011 Accepted for publication March 2011 S4 OMEPRAZOLE MUPS®: AN ADVANCED FORMULATION FOR SELF MEDICATION

many other enteric formulations have been produced (most delivering enteric coated pellets via a capsule), not all of these have the same release characteristics and this in turn could produce differences in bioavailability. Omeprazole products available for consumers to purchase cannot be considered interchangeable with regard to their pharmaceutical properties.

PHARMACOKINETICS AND PHARMACODYNAMICS OF THE OMEPRAZOLE MUPS® TABLET FOR THE TREATMENT OF ACID-RELATED SYMPTOMS - Prof. Dr. med. Karsten Schrör Direktor em, Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine Universität Düsseldorf, Germany

PHARMACOKINETICS

Omeprazole is an inactive prodrug that needs to be converted into an active form by nonenzymatic, proton-catalyzed generation of a sulphenamide intermediate. This non-chiral metabolite binds long-lastingly to the catalytic subunit of H+K+-ATPase in the secretory membranes of the parietal cells of the gastric mucosa.

The half-life of unmetabolized omeprazole is pH-dependent: in vitro at pH 1 it is 1-2 minutes but at pH 7.4 this increases to about 20 hours. In vivo, the plasma half-life of unmetabolized omeprazole is 1-2 hours while its half-life at the site of action is 24 hours. The short plasma half-life observed in vivo is due to clearance from the circulation by hepatic metabolism.

Omeprazole is a racemate and exists in two optical isomers in the S- and R-configuration. The S-isomer generates higher plasma-levels than the R-isomer, due to lower metabolic conversion by hepatic cytochromes (CYP2C19). The active molecular species, the sulphenamide, is non- chiral and equipotent after generation from both isomers. Thus, higher bioavailability and not higher intrinsic activity of the S-isomer (as in esomeprazole) explains the stronger inhibitory action of S-omeprazole observed at the molecular target site inside the parietal cells.

BIOAVAILABILITY

The omeprazole MUPS® tablet (omeprazole magnesium) was an innovative formulation developed in order to offer increased convenience, flexibility and predictability of absorption over omeprazole capsules. MUPS® tablets are small and easily swallowed and can be dispersed in water for people that have trouble swallowing solid forms. Each MUPS® tablet is comprised of about 1,000 individually coated micropellets. The tablet disintegrates rapidly in the stomach and the coated pellets are emptied into the duodenum where the absorption of omeprazole takes place. As previously noted, omeprazole is more stable at the high pH of the duodenum/ jejunum, than at the acid pH of the stomach. Studies using gamma scintigraphy confirm that micropellets empty more quickly into the duodenum than single unit dosage forms, particularly in the fed state4. This might result in faster bioavailability and therefore longer maintenance of gastric pH at or above pH 4 (the critical threshold for mucosal healing) than would occur with single-unit enteric-coated formulations of the drug.

©SELFCARE MAY 2011 Accepted for publication March 2011 S5 OMEPRAZOLE MUPS®: AN ADVANCED FORMULATION FOR SELF MEDICATION

Studies comparing the bioavailability of the MUPS® tablet and the conventional capsule were performed after single dose administration of all three strengths, i.e. 10, 20, and 40mg. As the most frequently used dose, 20mg of omeprazole was chosen for a comparison after once daily dosing for six days5. All comparisons were performed in healthy male volunteers.

In these studies the area under the plasma concentration vs time curve (AUC) and maximum plasma concentration (Cmax) were evaluated as primary variables for extent and rate of bioavailability. Ninety percent confidence intervals (CI) were constructed for the ratios (tablet/ capsule) of the true mean values of AUC and Cmax. Bioequivalence was concluded since the 90% CI for both parameters was entirely within the limits (0.80-1.25) established for bioequivalence (tableBioequivalence 1). between Omeprazole MUPS tablets and Omeprazole capsules TABLE 1: BIOEQUIVALENCE BETWEEN OMEPRAZOLE MUPS® TABLETS AND OMEPRAZOLE CAPSULES (Adapted from Reference 5).

ratio 10 mg 20 mg (s.d.) 20 mg (r.d.) 40 mg tabl / caps (n = 32) (n = 28) (n = 28) (n = 32)

AUC

estimate 1.01 1.02 1.06 0.97 (90% CI) (0.92 – 1.11) (0.94 – 1.11) (0.95 – 1.17) (0.88 – 1.06)

Cmax

estimate 1.00 1.05 1.03 0.97 (90% CI) (0.87 - 1.15) (0.90 - 1.21) (0.90 – 1.17) (0.85 – 1.12)

s.d.: single dose; r.d.: repeated dosing (day 6)

It is notable, however, that the plasma concentration/time (Långström etcurve al, Gastroenterology for both formulations114, AGA abstract G0228) are not identical and are influenced by food intake (Figure 4) with the MUPS® formulation producing faster absorption in the fed state. Plasma concentrations of Omeprazole after 20 mg single FIGURE 4: PLASMAdose CONCENTRATIONS administration OF OMEPRAZOLE as MUPS AFTER tablet 20MG or SINGLE capsule DOSE ADMINISTRATION AS MUPS® TABLET OR CAPSULE (Data on file AstraZeneca - reproduced with permission).

600 Omeprazole MUPS® tablet, 20 mg fasting 500 Omeprazole MUPS® tablet, 20 mg after food Omeprazole capsule, 20 mg 400

300

200

100

mean plasma concentration [nmol/l] concentration mean plasma 0 0 2 4 6 8 10 12 time [h]

( Bayer HealthCare) ©SELFCARE MAY 2011 Accepted for publication March 2011 S6 OMEPRAZOLE MUPS®: AN ADVANCED FORMULATION FOR SELF MEDICATION

Not long after the introduction of the MUPS® tablet, Geus et. al.6 described the pharmacokinetics of omeprazole MUPS® 20mg compared with pantoprazole 40mg (as single unit enteric-coated tablets) Medianfollowing plasma single (day concentrations 1) and repeated of (day Omeprazole 6) oral administration MUPS (20 and mg) compared the pharmacodynamicand Pantoprazole effect on (40gastric mg) pH at of dayboth 1 medicationsand day 6 on of these administration days (figure 5).

FIGURE 5: MEDIAN PLASMA CONCENTRATIONS OF OMEPRAZOLE MUPS® (20MG) AND PANTOPRAZOLE (40MG) AT DAY 1 AND DAY 6 OF ADMINISTRATION (Adapted from Reference 6).

0.5 Omeprazole 2.0 Pantoprazole

0.4 1.5

0.3 day 1 1.0 day 1 0.2 day 6 day 6

0.5 0.1 median plasma conc. [mg/l] median plasma conc. [mg/l] 0 0 0 2 4 6 8 0 2 4 6 8 time [h] time [h]

The area under the plasma concentration vs time curve (AUC) and maximum plasma (Geus et al, Aliment Pharmacol Ther 14: 1057 – 1064, 2000) concentration (Cmax) of omeprazole MUPS® (20mg) were slightly higher on day 6 as opposed to day 1 of administration: 74% vs 68% respectively. No pharmacokinetic differences were observed between day 1 and day 6 of administration for pantoprazole. The reasons for this difference, which had been described previously7, are unclear but it may result from saturation of first pass metabolism and/or a stepwise decrease in gastric acid delivered to the duodenum.

PHARMACODYNAMICS

A placebo-controlled comparison of acid inhibition on the first day of dosing in 18Helicobacter pylori-negative subjects compared 3 proton pump inhibitors (rabeprazole 20mg, lansoprazole 8 30mg, pantoprazoleMedian 40mg)pH monitoring with 20mg profileomeprazole on thedelivered first dayas capsules of proton or MUPS ® tablets . The gastric pHpump profiles inhibitor for both treatment dosage forms – comparison of omeprazole of wereOmeprazole similar (figure 6). capsule vs MUPS FIGURE 6: MEDIAN PH MONITORING PROFILE ON THE FIRST DAY OF PROTON PUMP INHIBITOR TREATMENT - COMPARISON OF OMEPRAZOLE CAPSULE VS MUPS® (Adapted from Reference 8).

drug administration breakfast lunch 5 Omeprazole 4 MUPS® (20 mg)

3 pH 2

1 Omeprazole capsule (20 mg) 0 800 900 1000 1100 1200 1300 1400 1500 1600

©SELFCARE MAY 2011 Accepted for publication March 2011 S7 (Pantoflickova et al, Aliment Pharmacol Ther. 17: 1507-1514, 2003) OMEPRAZOLE MUPS®: AN ADVANCED FORMULATION FOR SELF MEDICATION

The onset time of antisecretory action, or the first evidence of a statistically significant difference in the median pH values compared with the non-drug period (at 15-minute intervals during the first 6 hours), was 1.25 hours for omeprazole MUPS® tablet and 1.5 hours for omeprazole capsule, 1.75 hours for pantoprazole 40mg tablet and 1.75 hours for rabeprazole 20mg tablet. The authors propose that the differences in the onset of antisecretory action during the first 2 hours following drug administration can be explained by the different rates of absorption of the pro-drugs into the blood. This rate of absorption is related to the galenic formulations used, and absorption from enteric-coated tablet forms, which must first dissolve in the small intestine before absorption occurs, is delayed compared with that from small, individually coated, pellet dosage forms.

In the Geus study6 (conducted in 16 healthy Helicobacter pylori-negative subjects) day 6 median daytime pH was higher with omeprazole MUPS® (20mg) than with pantoprazole (40mg), possibly reflecting the higher bioavailability on repeated daily dosing with the former. However the percentage of time spent above pH 3 and 4 on day 6 was not significantly different between drugs.

SUMMARY

Omeprazole capsules and Omeprazole MUPS® are bioequivalent after single and repeated administration (day 6) at standard doses of 20mg. This bioequivalence is reflected in similar pharmacodynamic effects on gastric pH during the first day after dosing.

In a comparison in healthy subjects, there were no differences in acid inhibitory activity of omeprazole (20mg in a MUPS® tablet) and pantoprazole (40mg) on day 1, but a slightly higher median daytime pH with omeprazole MUPS® (20 mg) at day 6. This is of limited clinical relevance (since the times above pH 3 and 4 were similar for both drugs) but probably reflects the higher bioavailability of omeprazole on day 6 compared to day 1.

CONSUMER STUDIES ON PRILOSEC® OTC (OMEPRAZOLE MUPS® 20 MG) IN THE US PD Dr. med. Stephan R. Vavricka Head, Division of Gastroenterology and Hepatology, Stadtspital Triemli, Zurich, Switzerland

Of 100,000 adults: 40,000 will suffer reflux symptoms, but only rarely, 20,000 will suffer reflux symptoms weekly, 10,000 will have some grade of esophagitis, 400 will have Barrett’s esophagus and 2-4 will develop adenocarcinoma9. In the US a poll for the Gallup organisation found that 44% of those surveyed suffered heartburn at least once monthly and 18% took something for indigestion 2 or more times a week.

Recently, it has been proposed that 3 separate disease states represent three increasing degrees of severity on the spectrum of reflux disease: non erosive reflux disease (NERD), gastroesophageal reflux disease (GERD) and Barrett’s esophagus10. Most people with even

©SELFCARE MAY 2011 Accepted for publication March 2011 S8 OMEPRAZOLE MUPS®: AN ADVANCED FORMULATION FOR SELF MEDICATION

Efficacy of Prilosec OTCTM in frequent heartburn 109 frequent heartburn do not have erosive disease on endoscopy, and in the absence of ‘alarm’ Table 3.signsAnalysis or symptoms of primary (e.g. weight loss, dysphagia or anaemia), empirical treatment with a PPI is efficacy variable no heartburn Study 1 Ome-Mg 20 Ome-Mg 10 Placebo now recommended. Only if response to a PPI is Efficacyinadequate, of Prilosec should OTCTM inendoscopy frequent heartburn be considered.109 over 24 h across 14 days (intent-to- Heartburn-free 64Æ4% 60Æ8% 39Æ4% treat subjects)Table 3. Analysis of primary (mean% days) efficacyFor frequent variable no sufferers, heartburn completeStudy 1 and long-lastingOme-Mg relief 20of frequent Ome-Mg heartburn 10 is the Placeborequirement over 24 h across 14 days (intent-to- most frequently identified Heartburn-freein consumer research.64Æ4% 60Æ8% 39Æ4% treat subjects) Comparison P-value Difference in means 95% CI (mean% days) In the US, omeprazole hasOme-Mg been available 20 vs. placebo ‘over the counter’ <0Æ001 from 25 drugÆ0 stores since 2003.(21Æ1, The 28Æ8) Comparison P-value Difference in means 95% CI recommended dose is a 20mgOme-Mg (20.6 10 vs. mg placebo omeprazole <0magnesium)Æ001 21Æ4 MUPS® tablet daily(17 forÆ6, 2514Æ2) Ome-Mg 20 vs. Ome-Mg 10 0Æ068 3Æ6 ()0Æ3, 7Æ4) days in people with frequentOme-Mg symptoms 20 vs. placebo (2 or more <0daysÆ001 of heartburn 25Æ0 per week).(21 Æ1, 28Æ8) Ome-Mg 10 vs. placebo <0Æ001 21Æ4 (17Æ6, 25Æ2) StudyOme-Mg 2 20 vs. Ome-Mg 10Ome-Mg 0Æ068 20 3Æ6 Ome-Mg 10()0Æ3, 7Æ4) Placebo The efficacy of this regimen in the target group was demonstrated in two multi-centre, double- Study 2 Ome-MgÆ % 20 Ome-MgÆ % 10 Placebo Æ % Heartburn-free 67 8 61 4 11 37 9 blind placebo controlled randomised(mean% days) clinical studies of identical design . A total of 3162 subjects were randomised toHeartburn-free omeprazole MUPS®67 20mg,Æ8% omeprazole61Æ4 %MUPS® 10mg 37orÆ9 %matching (mean% days) placebo (study 1: 523 MUPSComparison® 20; 518 MUPS® 10; 519P-value placebo Difference and study in means2 524 MUPS 95%®CI 20; Comparison P-value Difference in means 95% CI 520 MUPS® 10; 520 placebo)Ome-Mg and 20 kept vs. placebo a diary for the <0Æ 00114 days 29 ofÆ8 treatment. One day(26Æ1, after 33Æ5) the first dose, nearly 50%Ome-Mg Ome-Mgof subjects 1020 vs. receiving placebo placebo MUPS <0Æ® <0001 20Æ001 reported 29Æ8 23Æ5 no heartburn.(26 ÆAcross1, 33(19Æ5) Æ7, both 27Æ2) Ome-MgOme-Mg 2010 vs. placebo Ome-Mg 10 <0Æ <0001Æ001 23Æ5 6Æ4 (19Æ7, 27Æ2)(2Æ7, 10Æ1) studies subjects on MUPS®Ome-Mg 20 reported 20 vs. Ome-Mg around 10 85% <0Æ 001of nights 6Æ4 as completely heartburn(2Æ7, 10Æ1) free over the 14 days of the studyP-values (P < are 0.001 from tvs-test, placebo) comparing and treatment suffered means no (difference more than in LS meansmild heartburn from ANOVA modelP-values using are fromtreatmentt-test, andcomparing investigator treatment as means factors). (difference in LS means from ANOVA on around 80% of the daytimemodel periods. using treatment (Figure and investigator 7). as factors). Estimated difference in mean% days heartburn-free (difference in LS means from ANOVA Estimated difference in mean% days heartburn-free (difference in LS means from ANOVA modelmodel using using treatment and and investigator investigator as factors). as factors). FIGURE 7 (Adapted from Reference95 11).95%%confidenceconfidence interval interval (two-sided) (two-sided) for for estimated estimated difference difference in means. in means.

Fig. 3. Percentage of subjects with no more than mild Percentage of nights with no nocturnal heartburn Percentage of days with no more than mild heartburn. Fig. 2. Percentage of nights with no nocturnal heartburn heartburn on day 1. over 14 days of therapy Fig. 3. Percentage of subjects with no more than mild over 14 days of therapy. Fig. 2. Percentage of nights with no nocturnal heartburn heartburn on day 1. over 1420 days and ofOme-Mg therapy. 10 were not signiﬁcantly differ- groups in both studies were very similar. Those entBoth from omeprazole each other for doses percentage were ofsignificantly days with reportedmore effective at incidences than placebo of >1% (allon belowdays 1 5%and) 14 for 20 andnopercentage Ome-Mg more than 10 mild of were subjects heartburn, not signiﬁcantlyheartburn-free although Ome-Mg differ- for 24included groupshours diarrhoea,(P in < both or = studies headache,0.003), were and infections/respirat- veryacross similar. all 14 Thosedays ent from20for was each percentage numerically other for of superior percentage heartburn-free to Ome-Mg of days days 10 with on(P < 0.001).oryreported infections, The atauthors abdominal incidences concluded pain of and >1 that% nausea/vom-(all this below degree 5 %of) no moreday 1 than and mildacross heartburn, all 14 days of although the study Ome-Mg (Fig. 4). iting.included Subjects diarrhoea, provided headache, serum chemistry infections/respirat- and 20 wasefficacy numerically and superiorthe good totolerability Ome-Mg 10evident on in haematologyorythe study, infections, confirmed samples abdominal at baselineomeprazole pain and nausea/vom- atMUPS® the20mg as completion of the double-blind treatment phase of day 1Safety andan excellent across results all choice 14 days for of self the care study of (Fig. frequent 4). heartburn.iting. Subjects provided serum chemistry and the study; all treatment groups were similar with Overall, Ome-Mg was very well tolerated. The respecthaematology to change samples from baseline at for baseline all values and and at the In the US, OTC status means that individuals cancompletion self–select of treatments the double-blind from drug treatment store phaseshelves of Safetymost results common adverse events across all treatment no subject had clinically concerning laboratory and must rely on the product label to guide thecorrect study; use all of treatment the medicine. groups Often were similarstudies withare Overall,Ó 2005 Ome-Mg Blackwell Publishing was very Ltd, Journal well of Clinicaltolerated. Pharmacy The and Therapeuticsrespect, 30, 105–112 to change from baseline for all values and performed to demonstrate that the product label achieves the purpose of appropriate selection most common adverse events across all treatment no subject had clinically concerning laboratory and usage of the drug according to the label restrictions in place. Such a naturalistic ‘actual Ó 2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 105–112

©SELFCARE MAY 2011 Accepted for publication March 2011 S9 OMEPRAZOLE MUPS®: AN ADVANCED FORMULATION FOR SELF MEDICATION

use’ study was reported by Fendrick et al in 200412. In this 3 month observational study 1999 subjects with heartburn were exposed to the product in a ‘shopping mall’ environment; of these 866 purchased the medicine. A high proportion of this number (88%) returned a diary for analysis. The aims of the study were to answer the following questions:

• Do consumers correctly self-select to use omeprazole? • Do consumers comply with the product label (14 days of once-daily dosing)? • Do consumers use more than 14 doses of medication only under the advice of a physician?

Subjects accurately self-selected themselves as frequent sufferers: more than 90% of participants had heartburn 2 or more days/week. Diary data demonstrated a high degree of compliance to label directions and only 3% of subjects took more than 14 doses without consulting a physician. After 3 months, 43% of subjects did not have recurrence of their heartburn, confirming that a 14 day treatment with omeprazole can have lasting effects in this patient population. The majority (75%) of subjects had contact with a physician about heartburn before, during, or soon after the study (26% during the 3-month study). Therefore, at least in the US, frequent heartburn is most often not treated completely without advice. Since a trial of empirical PPI treatment is the most likely outcome of consultation, this seems an acceptable pattern of usage when there are no ‘alarm’ symptoms present and response is satisfactory.

Lansoprazole at a dose of 15mg is now available OTC in the US for the same indication as omeprazole MUPS® 20 (omeprazole magnesium 20.6mg). Recently the pharmacodynamics of these doses have been compared in a 3 period, double blind, cross over design study of 24 hours steady state gastric acid suppression (on day 5 of dosing) in 40 healthy volunteers13. The primary efficacy variable was the percentage time intragastric pH was >4.0 over 24 hours on day 5 of dosing.

The mean (SE) percentage time pH was >4.0 was 45.7% (3.45%) for omeprazole MUPS® 20.6mg and 36.8% (3.45%) for lansoprazole 15mg, an absolute difference of 8.9% (P < 0.0001), and a relative difference of 24.2%. Figure 8 shows the distribution of subject treatment ratios for the percentage time pH >4.0 in 24 hours.

SUMMARY

Omeprazole magnesium formulated as MUPS® tablets is available for self selection in US drugstores for individuals with frequent heartburn. Studies confirm the good performance of omeprazole MUPS® 20mg in producing complete relief of heartburn during 14 days of treatment. A large ‘actual use’ study mimicking the OTC setting, confirmed that individuals were able to appropriately select themselves as suitable for the treatment and very few (3%) exceeded 14 days treatment without a doctor’s advice. Finally comparison with a recently approved competitor PPI (lansoprazole 15mg) confirms statistically greater acid suppression at steady state (day 5) with omeprazole MUPS® 20mg.

Table 2. Percentage time that gastric pH was greater than speciﬁed pH threshold. Data are for 40 subjects, 118 24-h pH recordings

Mean (S.E.)*

pH Omeprazole-Mg Lansoprazole Difference Relative percentage threshold 20.6 mg 15 mg mean (S.E.)* P-value* difference

>2.0 72.6 (2.81) 62.8 (2.81) 9.8 (1.89) <0.0001 15.6% >3.0 58.5 (3.33) 47.7 (3.33) 10.8 (2.17) <0.0001 22.7% >4.0à 45.7 (3.45) 36.8 (3.45) 8.9 (2.10) <0.0001 24.2% >5.0 30.9 (3.32) 25.2 (3.32) 5.8 (1.83) 0.0023 23.0%

* Calculated from cross-over ANOVA model. Calculated as [(Omeprazole-MgOMEPRAZOLE MUPS®:)Lansoprazole) AN ADVANCED FORMULATION⁄ Lansoprazole]100%. FOR SELF MEDICATION à Prospectively deﬁned primary endpoint.

FIGURE 8 (Adapted from Reference 13). 10 gastric pH was greater than 4.0 over 24-h on day 5 of Omeprazole-Mg better dosing, was signiﬁcantly greater with omeprazole-Mg 8 Lansoprazole better (45.7%) on average than with lansoprazole (36.8%), an absolute difference of 8.9% (P < 0.0001) and a relative 6 difference of 24.2%. For perspective, the absolute treat- 4 ment difference of 8.9% observed in the current study is comparable to the differences reported in a previous

Number of subjects 2 study that compared percentage time gastric pH was greater than four for esomeprazole 40 mg (58%) vs. lan- 0 soprazole 30 mg (48%), omeprazole 20 mg (49%) and 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 rabeprazole 20 mg (51%).6 Treatment ratio % time pH > 4 This difference in gastric acid control for omepra- Distribution of within subject treatment ratios for the percentage time pH>4.0 in 24 h ( ie. percentage time for omeprazole-Mg / percentage of time for lansoprazole). For 29 subjects, the ratio was >1 (i.e. the percentage timezole-Mg vs. lansoprazole was evident across the 24-h pH >4 was greaterFigure for omeprazole-Mg 3. Distribution than for lansoprazole). of within For subject 10 subjects, treatment the ratio was ratios<1. (i.e. percentage period when median gastric pH was plotted by treat- time pH >4 was lessfor for the omeprazole-Mg percentage than timefor lansoprazole). pH >4.0 In in one 24 subject h. Forthe response each subject,was equal. a ratio (omeprazole-Mg effect ‚ lansoprazole) was calcu- ment (Figure 1). Note that the median pH for omepra- lated for percentage time pH >4. The figure is a histogram zole-Mg was higher than lansoprazole for a clear CLINICAL EFFICACYof these OF ratios OMEPRAZOLE for all 40 MUPS® subjects, IN THE with NETHERLANDS a total of 118 AND 24- SOME majority of the post-prandial periods. The 24-h med- CONSIDERATIONSh pH RELATING recordings. TO For GENERIC 29 subjects, SUBSTITUTION the ratio – Prof. was Chris >1 (i.e. J.J. Mulder, the MDian PhD gastric pH was maintained at a significantly higher percentage time pH >4 was greater for omeprazole-Mg VU University Medical Center, Department of Gastroenterology and Hepatology, Amsterdamlevel for omeprazole-Mg (3.685) vs. lansoprazole than for lansoprazole). For 10 subjects, the ratio was <1 (i.e. percentage time pH >4 was less for omeprazole-Mg (3.058) (P < 0.0001). SYMPTOMATIC EFFICACY OF PPIS IN THE TREATMENT OF REFLUX ESOPHAGITIS than for lansoprazole). One subject had an equal response At least two factors may have contributed to the Proton pumpto inhibitors both drugs. (PPIs) have proved to be effective in treating refluxsuperior oesophagitis acid control observed for omeprazole-Mg over and healing erosive disease. However relatively few studies have compared the symptomaticlansoprazole. The first factor is the relative doses efficacy of PPls directly in such patients. A double blind multicentre study in the Netherlandstested in14 this study, which are the approved OTC doses randomised patients with symptomatic grade I-IV reflux oesophagitis to omeprazolein theMUPS United® States. Omeprazole was approved for DISCUSSION 20mg, lansoprazole 30mg and pantoprazole 40mg, all dosed daily in the morning. OTC use at the same level as the most commonly used ) Patient satisfactionThis study and symptoms demonstrated were evaluated that omeprazole-Mg after 4 and 8 weeks. 20.6 Patients mg notprescription satisfied dose 20 mg. Although more than 90% of after 8 weeksprovided were treated a statistically for another 4 significantly weeks with omeprazole (P < 0.0001) 40mg MUPSthe® (open). prescriptions for lansoprazole were for a 30 mg Successful greatertreatment control was followed of gastric by 3 acidmonths production of maintenance at steady treatment state with omeprazoledose, the approved OTC dose of 15 mg lansoprazole is MUPS® 20mgthan (in lansoprazolepatients satisfied 15 after mg. 4 Bothor 8 weeks) drugs or were omeprazole dosed dailyMUPS® 40mgonly (patients half of that level. A second possible contributing satisfied afterbefore 12 weeks). breakfast, consistent with OTC label instructions, factor is the relative potency of the two drugs. A with all 40 subjects completing the cross-over study and recent meta-analysis of 57 clinical studies assessed the On intention-to-treat98% of the analysis 24-h (n gastric = 461) pH at recordings 4 and 8 weeks, included respectively, in the 84%relative and 87% potency of marketed PPIs.8 Using omeprazole (omeprazole MUPS®), 78% and 81% (lansoprazole), and 84% and 89% (pantoprazole) were data analysis. The primary variable, percentage of time as the test standard (relative potency 1.0), the authors free of heartburn. These results were reflected in ratings of patient satisfaction with treatment after 4 and 8 weeks, and this was similar in all treatment groups. During maintenance, 87% Aliment Pharmacol Ther 31, 846–851 in the omeprazole MUPS® 20mg group and 81% in the omeprazole MUPS® 40mg group were ª 2010 Blackwell Publishing Ltd satisfied after 3 months.

Omeprazole MUPS® 20mg and pantoprazole 40mg have similar efficacy in the treatment of reflux oesophagitis. Based on patient satisfaction, all three drugs in this study were equally effective at these doses.

SOME CONSIDERATIONS RELATING TO GENERIC SUBSTITUTION OF PPIS

Proton pump inhibitors are the most effective acid suppressive drugs. They are widely used for gastroesophageal reflux disease, ulcer disease, anti-H.pylori therapy, and as protective agents when chronic NSAID therapy is needed. Surveys of usage have shown substantial growth in recent years and the cost of this in turn creates pressure to use the least expensive drugs. Since 2004, when the patent expired for omeprazole, more than 50 generic preparations have been launched in the Netherlands.

To be launched as a generic equivalent to the originator drug, a formulation has to show bioequivalence according to a standardised definition. The area under the plasma concentration vs time curve (AUC) and maximum plasma concentration (Cmax) are evaluated as primary variables for extent and rate of bioavailability. Ninety percent confidence intervals (CI) are constructed for the ratios (generic vs originator) of the true mean values of AUC and Cmax. Bioequivalence can be concluded if the 90% CI is entirely within the limits (0.80-1.25) established as representing effective bioequivalence. As long as this condition is met, generics can differ with respect to pharmaceutical form (pills, capsules, pellets, salts and excipients), pattern of bioavailability, and pharmacokinetics. When, as with omeprazole, the delivery of a pro-drug to the site of activation is crucially dependant on properties such as gastroresistance of the formulation, differences in clinical effect are plausible for different galenic formsof the same drug. Studies examining dissolution of formulations in a pH of 1 and 3 (pH in the stomach) and dissolution in a pH of 6.8 (pH in the small intestine) after prior exposure to low pH, confirm that not all behave in the same way15. Although ultimately all products may release the same amount of active compound, the pattern of release varies markedly and ‘dose dumping’ can occur when drug is released very quickly.

Not all proton pumps are activated at the same moment, but an activated proton pump is required for the protonation of the pro-drug. Only the activated pro-drug can block the proton pump. Hence ‘dose dumping’ will result in blockage of only a small number of pumps that are active while the majority of the pro-drug may leave the body without any effect on the “sleeping” or currently inactivated proton pumps.

Bio-equivalency is based on static numbers retrieved from experiments with healthy volunteers, often after one dose of the active compound. However pharmacodynamic effects may vary over time, for example in relation to changes in bioavailability with multiple dosing, as has been observed with omeprazole6. Ultimately, the only way to evaluate the efficacy of an active compound is to study clinical outcome parameters. Typically only the originator drug is studied extensively with regard to pharmacodynamic effect and clinical efficacy. Comparisons between

originator and generic products are only valid for the formulation chosen, and with multiple generic forms available, such comparisons have limited utility and so are seldom performed.

In a survey of generic drug usage in the Netherlands, amongst 5254 users of generic omeprazole 7.9% switched to Losec® and 11.7% switched to another PPI because of lack of or unsatisfactory efficacy15. In contrast, in a ‘control’ group only 1.1% of patients on generic paroxetine needed to be switched to Seroxat®. Thus approximately 20% of individuals did not appear to achieve a satisfactory response on generic omeprazole. This lack of a predictable response has the potential to increase the hidden costs associated with increased consultations and the endoscopies that might result.

SUMMARY

Omeprazole MUPS® 20mg provided effective symptomatic relief equivalent to the newer PPIs lansoprazole 30mg and pantoprazole 40mg in patients with grade I-IV reflux oesophagitis treated for 4-8 weeks.

Surveys of generic omeprazole usage in the Netherlands suggest a relatively high level of dissatisfaction (around 20%) requiring substitution by the originator product or an alternative PPI. This in turn suggests that some usage of generic omeprazole represents a false economy and may result in increased hidden costs. Many factors influence the availability of omeprazole at the site of its activation and this can be profoundly influenced by the formulation of the drug for oral delivery. With this drug in particular, a limited definition of bioequivalence on pharmacokinetic grounds may not predict pharmacodynamic and clinical response adequately. In the absence of pharmacodynamic and clinical evaluations of generic formulations, health care professionals should not assume that all omeprazole formulations are the same and they may want to advise consumers purchasing OTC drugs accordingly.

Financial Statement: This paper reports the proceedings of an invited meeting sponsored by Bayer Consumer Care AG, Basel, Switzerland. Jérôme Aubert is an employee of Bayer Santé Familiale S.A.S., France; Karsten Schrör, Stephan R. Vavricka and Chris J.J. Mulder were sponsored to attend the meeting by Bayer Consumer Care.

REFERENCES

1. El-Sayed A, Boraie NA, Ismail FA, El-Khordagui LK, Khalil SA. Assessment of the pharmaceutical quality of omeprazole capsule brands marketed in Egypt. East Mediterr Health J. 2007 Nov-Dec;13(6):1427-37.

2. Palummo M, Cingolani A, Dall L, Volonté MG. Stability of capsules containing omeprazole in enteric coated pellets. Boll Chim Farm. 2000 May-Jun;139(3):124-8.

3. Storpirtis S, Rodrigues D. In vitro evaluation of dissolution properties and degradation products of omeprazole in enteric-coated pellets. Drug Dev Ind Pharm.1998 Nov;24(11):1101-7.

4. Davis SS, Hardy JG, Fara JW. Transit of pharmaceutical dosage forms through the small intestine. Gut. 1986 Aug;27(8):886-92.

5. Anderberg E-K, Cullberg M, Långström G et al. Bioequivalence between omeprazole MUPS tablets and omeprazole capsules. Gastroenterology 1998 114, AGA abstract G0228

6. Geus WP, Mathôt RA, Mulder PG, Lamers CB. Pharmacodynamics and kinetics of omeprazole MUPS 20 mg and pantoprazole 40 mg during repeated oral administration in Helicobacter pylori-negative subjects. Aliment Pharmacol Ther. 2000 Aug;14(8):1057-64.

7. Andersson T, Andren K, Cedeberg C, Lagerstrom PO, Lundborg P, Skanberg I. Pharmacokinetics and bioavailability of omeprazole after single and repeated oral administration in healthy subjects. Br J Clin Pharmacol 1990; 29: 557-63.

8. Pantoflickova D, Dorta G, Ravic M, Jornod P, Blum AL. Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors. Aliment Pharmacol Ther. 2003 Jun 15;17(12):1507-14.

9. Locke GR 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ 3rd. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology. 1997 May;112(5):1448-56

10. Fass R, Ofman JJ. Gastroesophageal reflux disease--should we adopt a new conceptual framework? Am J Gastroenterol. 2002 Aug;97(8):1901-9. Review.

11. Allgood LD, Grender JM, Shaw MJ, Peura DA. Comparison of Prilosec OTC (omeprazole magnesium 20.6 mg) to placebo for 14 days in the treatment of frequent heartburn. J Clin Pharm Ther. 2005 Apr;30(2):105-12.

12. Fendrick AM, Shaw M, Schachtel B, Allgood L, Allgood G, Grender J, Peura D. Self-selection and use patterns of over- the-counter omeprazole for frequent heartburn. Clin Gastroenterol Hepatol. 2004 Jan;2(1):17-21.

13. Miner PB Jr, McKean LA, Gibb RD, Erasala GN, Ramsey DL, McRorie JW. Omeprazole-Mg 20.6 mg is superior to lansoprazole 15 mg for control of gastric acid: a comparison of over-the-counter doses of proton pump inhibitors. Aliment Pharmacol Ther. 2010 Apr;31(8):846-51. Epub 2010 Feb 8.

14. Mulder CJJ, Westerveld BD, Smit JM, Oudkerk Pool M, Otten MH, Tan TG, van Milligen de Wit AWM and de Groot GH, on behalf of the Dutch omeprazole MUPS study group. A double-blind, randomized comparison of omeprazole Multiple Unit Pellet System (MUPS) 20 mg, lansoprazole 30 mg and pantoprazole 40 mg in symptomatic reflux oesophagitis followed by 3 months of omeprazole MUPS maintenance treatment: a Dutch multicentre trial. Eur J Gastroenterol Hepatol 2002, 14: 649–656

15. Tahmassian R, van der Zee PH. De patient had toch gelijk – Generiek omeprazol heeft andere afgifte dan specialité (The patient is thus right – Generic omeprazole has a different release than the original). Pharmaceutisch Weekblad 2005, 26/27: 877-878